It is often desirable in the surgical field, and particularly in the field of microsurgery, such as ophthalmological surgery, to introduce stains, dyes or colorants (referred to collectively as “colorant”) into a surgical site of a patient in order to enhance visual detail of the site. A suitable colorant must be biocompatible with the patient. For instance, it must be generally nontoxic and exhibit a pH compatible with the patient. Moreover, it must exhibit sufficient viscosity, surface and wetting characteristics so that it can be suitably directed to the region of interest, upon being administered to the patient.
A number of commercially available biocompatible colorants exist in the medical field, as the skilled artisan will appreciate. Without limitation, an example of one type of colorant that has attracted attention for certain applications is indocyanine green. That colorant has been used successfully in certain procedures, such as retinal angiograms, and other imaging studies of organs, owing largely to its ability to fluoresce, such as upon being suitably excited from an external energy source. U.S. Pat. Nos. 5,804,448 (Wang, et al); 5,576,013 (Williams, et al); 5,377,686 (O'Rourke et al); and 5,279,298 (Flower), all of which are expressly incorporated by reference herein.
Only recently has it been suggested that indocyanine green be used as an adjunct to cataract surgery to aid in visualizing the anterior capsule (the clear “front” membrane that encases the cloudy natural lens or “cataract”), in certain special cases where the anterior capsule is otherwise difficult to resolve optically. Though other colorants have been attempted for limited use in cataract surgery, the use of such colorants (for cataract surgery or other ophthalmological surgical procedures) still remains largely unexplored. Consequently, efficacy and other biocompatibility data is lacking or is dubious, i.e., is limited to highly specific conditions.
Moreover, it is believed that the use of a colorant such as indocyanine green has never been attempted for retinal surgery procedures. Recently, surgical removal or peeling of the internal-limiting membrane (“ILM”) has been described as a potentially useful adjunct to vitreoretinal surgery, particularly in select macular hole cases, or other disorders characterized by an abnormal vitreoretinal interface. Typically, when the ILM is peeled, there are only subtle visible clues if any to determine the location of the border between unpeeled ILM and adjacent underlying retina or to define the best edge for continued peeling of the ILM. For example, where the ILM has been peeled, the underlying retina often acquires a rough or dull sheen, and there are often small intraretinal hemorrhages within the peeled area. However, it may be difficult to initiate the ILM peel and to visualize the border or edge of the membrane once ILM peeling has been started. It may also be difficult to continue an ILM peel if the edge is lost, or to determine the total extent of a peel (including from prior operations). Thus, difficult visualization of the ILM as well as firm attachment of the ILM to the underlying layers of the retina present potential technical challenges when trying to peel this membrane.
Ophthalmological surgery poses other unique constraints on the successful use of colorants to aid optical resolution. For example, the necessary tonicity of the colorant and any carrier that is used to deliver the colorant to the eye requires precise control over the composition and concentration of the colorant/carrier admixture. Some commercially available components for the admixture are provided as two-component systems (e.g., a granular precipitate and a solvent) that must be mixed in suitable proportions before administering to the patient. Moreover, the colorant systems typically have a relatively short shelf-life (e.g., commercially available indocyanine green commonly is marketed as having a fluorescence stability of only about 10 hours upon mixing).
References of potential interest to the present invention, all of which are expressly incorporated by reference, include:                Fine, B S. Limiting membranes of the sensory retina and pigment epithelium: an electron microscopic study. Arch Ophthalmol 1961;66:847–60.        Clarkson J G, Green W R, Massof D. A histopathologic review of 168 cases of preretinal membrane. Am J Ophthalmol 1977;84:1–17.        Michels R G. A clinical and histopathologic study of epiretinal membranes affecting the macula and removed by vitreous surgery. Tr Am Ophthalmol Soc 1982;80:580–656.        Smiddy W E, Green W R, Michels R G, de la Cruz Z. Ultrastructural studies of vitreomacular traction syndrome. Am J Ophthalmol 1989;107:177–85.        Smiddy W E, Michels R G, de Bustros S, et al. Histopathology of tissue removed during vitrectomy for impending macular holes. Am J Ophthalmol 1989;108:360–4.        Smiddy W E, Michels R G, Green W R. Morphology, pathology, and surgery of idiopathic vitreoretinal disorders. A review. Retina 1990;10:288–296.        Guyer D R, Green W R, de Bustros S, Fine S L. Histopathologic features of idiopathic macular holes and cysts. Ophthalmology 1990;97:1045–51.        Zarbin M A, Michels R G, Green W R. Epiretinal membrane contracture associated with macular prolapse. Am J Ophthalmol 1990;110:610–8.        Park D W, Sipperley J O, Sneed S R, et al. Macular hole surgery with intemal-limiting membrane peeling and intravitreous air. Ophthalmology 1999;106:1392–8.        Eckardt C, Eckardt U, Groos S, et al. Removal of the internal limiting membrane in macular holes. Ophthalmologe 1997;94:545–51.        Olsen T W, Sternberg P Jr, Capone A Jr, et al. Macular hole surgery using thrombin-activated fibrinogen and selective removal of the internal limiting membrane. Retina 1998;18:322–9.        Yoon H S, Brooks H L, Jr, capone A Jr, et al. Ultrastructural features of tissue removed during idiopathic macular hole surgery. Am J Ophthalmol 1996;122:67–75.        Maguire A M, Smiddy W E, Nanda S K, et al. Clinicopathologic correlation of recurrent epiretinal membranes after previous surgical removal. Retina 1990;10:213–22.        Livingstone, B I, Bourke, R D. A retrospective study of macular holes with pars plana vitrectomy. Aust N Z J Ophthalmol 1999; in press.        Hope-Ross M, Yannuzzi L A, Gragoudas E S, et al. Adverse reactions due to indocyanine green. Ophthalmology 1994; 101:529–33.        Lutty G A. The acute intravenous toxicity of biological stains, dyes, and other fluorescent substances. Toxicol Appl Pharmacol 1978;44:225–49.        Destro M, Puliafito C A. Indocyanine green videoangiography of choroidal neovascularization. Ophthalmology 1989;96:846–53.        Yannuzzi L A, Slakter J S, Sorenson J A, et al. Digital indocyanine green videoangiography and choridal neovascularization. Retina 1992;12:191–223.        Guyer Dr, Puliafito C A, Mones J M, et al. Digital indocyanine-green angiography in chorioretinal disorders. Ophthalmology 1992;99:287–91.        Ho A C, Yannuzzi L A, Guyer D R, et al. Intraretinal leakage of indocyanine green dye. Ophthalmology 1994;101:534–41.        McEnerney J K, Peyman G A. Indocyanine green: a new vital stain for use before penetrating keratoplasty. Arch Ophthalmol 1978;96:1445–7.        Horiguchi M, Miyake K, Ohta I, Ito Y. Staining of the lens capsule for circular continuous capsulorrhexis in eyes with white cataract. Arch Ophthalmol 1998;116:535–7.        Smiddy W E. Discussion of: Park D W, Sipperley J O, Sneed S R, et al. Macular hole surgery with internal-limiting membrane peeling and intravitreous air. Ophthalmology 1999;106:1397–8.        Erza E, Aylward W G, Gregor Z J. Membranectomy and autologous serum for the retreatment of full-thickness macular holes. Arch Ophthalmol 1997;115:1276–80.        Ferris J D. Pathogenesis of idiopathicmacular holes. Current Opin Ophthalmol. 1997;8:87–93.        Weingeist T A, Goldman E J, Folk J C, et al. Terson's syndrome. Clinicopathologic correlations. Ophthalomogy 1986;93:1435–42.        Russell S R, Hageman G S. Hemorrhagic detachment of the internal limiting membrane after penetrating ocular injury. Retina 1992;12:346–50.        Friedman S M, Margo C E. Bilateral subintemal limiting membrane hemorrhage with Terson syndrome. Am J Ophthalmol 1997;124:850–1.        